PMID- 12851689
OWN - NLM
STAT- MEDLINE
DCOM- 20040304
LR  - 20181219
IS  - 1019-6439 (Print)
IS  - 1019-6439 (Linking)
VI  - 23
IP  - 2
DP  - 2003 Aug
TI  - Thymidine and hypoxanthine protection patterns of the folic acid-enhanced 
      synergies for combinations of trimetrexate plus a polyglutamylatable inhibitor of 
      purine or thymidylate synthesis against human ileocecal HCT-8 cells.
PG  - 401-9
AB  - In order to examine the intracellular locus of the folic acid (PteGlu)-enhanced 
      synergies of trimetrexate (TMQ) plus the thymidylate synthase (TS) inhibitor, 
      raltitrexed (RTX), and TMQ plus the glycinamide ribonucleotide formyltransferase 
      (GARFT) inhibitor, AG2034, comprehensive protection studies with thymidine (dThd) 
      and hypoxanthine (HX) were conducted in a 96-well plate cell growth inhibition 
      (sulforhodamine B) assay. Current modeling techniques were extended to 
      characterize these protection patterns involving multiple-agent interaction. 
      Wild-type human ileocecal HCT-8 cells and DW2, a subline deficient in 
      folylpoly-gamma-glutamate synthetase (FPGS) were individually treated for 96 h 
      with TMQ, AG2034 and a 1:1 mixture of TMQ:AG2034 or with TMQ, RTX, and a 1:1 
      mixture of TMQ:RTX in the presence of PteGlu (2.3 or 40 micro M) and the 
      protection agents (10 micro M dThd and/or 100 micro M HX). Drug treatments were 
      randomly assigned to wells. Both isobols and 3-dimensional concentration-effect 
      surfaces were used to assess the nature and the intensity of drug interactions. 
      The structural Hill model was fitted to data with weighted non-linear regression 
      for most cases. A so-called 'double Hill' model was sometimes more appropriate 
      when a plateau in the middle of the concentration-effect curve was found. In 
      HCT-8 and DW2 cells at 2.3 and 40 micro M PteGlu, inhibition of DHFR by TMQ 
      induced antithymidylate and antipurine effects; AG2034 and RTX selectively 
      inhibited de novo purine or thymidine synthesis, respectively. dThd protection 
      increased the PteGlu-enhancement of the TMQ + AG2034 synergy, whereas HX 
      protection increased the PteGlu-enhancement of the TMQ + RTX synergy. The 
      PteGlu-enhanced synergies of TMQ + AG2034 and TMQ + RTX occur primarily through 
      inhibition of purine synthesis and inhibition of thymidylate synthesis, 
      respectively. These results further substantiate the hypothesis that the 
      nonpolyglutamylatable DHFR inhibitor, TMQ, acts as a modulator by decreasing the 
      protection by PteGlu of cells against the polyglutamylatable AG2034 and RTX.
FAU - Faessel, Helene M
AU  - Faessel HM
AD  - Groton Laboratories, Pfizer Inc., Clinical PK-PD, Groton, CT 06340, USA.
FAU - Slocum, Harry K
AU  - Slocum HK
FAU - Rustum, Youcef M
AU  - Rustum YM
FAU - Greco, William R
AU  - Greco WR
LA  - eng
GR  - CA16056/CA/NCI NIH HHS/United States
GR  - CA65761/CA/NCI NIH HHS/United States
GR  - RR10742/RR/NCRR NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Glutamates)
RN  - 0 (Hematinics)
RN  - 0 (Pyrimidines)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - 2TN51YD919 (Hypoxanthine)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - EC 2.1.2.- (Hydroxymethyl and Formyl Transferases)
RN  - EC 2.1.2.2 (Phosphoribosylglycinamide Formyltransferase)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.3.2.17 (folylpolyglutamate synthetase)
RN  - FCB9EGG971 (raltitrexed)
RN  - IC32U30905 (AG 2034)
RN  - UPN4ITI8T4 (Trimetrexate)
RN  - VC2W18DGKR (Thymidine)
SB  - IM
MH  - Adenocarcinoma/*drug therapy/*metabolism
MH  - Antineoplastic Agents/pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Cecal Neoplasms/drug therapy/metabolism
MH  - Cell Division/drug effects
MH  - Drug Resistance, Multiple
MH  - Drug Synergism
MH  - Enzyme Inhibitors/pharmacology
MH  - Folic Acid/*pharmacology
MH  - Glutamates/adverse effects
MH  - Hematinics/pharmacology
MH  - Humans
MH  - Hydroxymethyl and Formyl Transferases/antagonists & inhibitors
MH  - Hypoxanthine/metabolism/*pharmacology
MH  - Ileal Neoplasms/drug therapy/metabolism
MH  - Peptide Synthases/deficiency
MH  - Phosphoribosylglycinamide Formyltransferase
MH  - Pyrimidines/adverse effects
MH  - Quinazolines/pharmacology
MH  - Thiophenes/pharmacology
MH  - Thymidine/metabolism/*pharmacology
MH  - Thymidylate Synthase/antagonists & inhibitors
MH  - Trimetrexate/adverse effects
MH  - Tumor Cells, Cultured
EDAT- 2003/07/10 05:00
MHDA- 2004/03/05 05:00
CRDT- 2003/07/10 05:00
PHST- 2003/07/10 05:00 [pubmed]
PHST- 2004/03/05 05:00 [medline]
PHST- 2003/07/10 05:00 [entrez]
PST - ppublish
SO  - Int J Oncol. 2003 Aug;23(2):401-9.